Prevalence of symptomatic skeletal events (SSE) with reduced denosumab (Dmab) dose density (every 12 weeks versus every 4 weeks): A randomized phase III non-inferiority trial SAKK 96/12 REDUSE.

1004 Background: Clinical guidelines recommend Dmab 120 mg every 4 weeks (Q4W) for patients (pts) with bone metastases. While dosing every 12 weeks (Q12W) is established for zoledronic acid based on phase III trials, prospective trials with Dmab evaluating the efficacy endpoint of skeletal-related events (SRE) for a Q12W schedule are missing. The results of an early dose-finding study of Dmab demonstrated a similar suppression of bone-turnover markers for 60 mg Q12W as for 120 mg Q4W at weeks 13 and 25, suggesting that Q12W dosing might be sufficient. The SAKK 96/12 REDUSE trial investigated whether a de-escalated Dmab schedule is non-inferior to the standard Q4W regimen in preventing symptomatic skeletal related events (SSEs; symptomatic pathological fracture, radiation or surgery to bone, or spinal cord compression). Methods: In this international, multicenter, randomized, phase III trial, pts with metastatic breast cancer (BC) or castration-resistant prostate cancer (CRPC) and at least three bone metastases were randomized 1:1. Arm A (standard) received Dmab 120 mg Q4W. Arm B (reduced) received 4 loading doses Q4W, followed by Q12W dosing. The primary endpoint was time to first on-trial SSE. The sample size of 1,380 pts was calculated to demonstrate non-inferiority using a log-rank test with a non-inferiority margin of 1.20 (80% power, 5% type I error). Secondary endpoints included time to first and subsequent on-trial SSE, and toxicity focusing on hypocalcemia and osteonecrosis of the jaw (ONJ). A health economic analysis is ongoing. Results: 1,380 pts were enrolled between 7/2014 and 3/2024 (784 and 596 with BC and CRPC, respectively). Median follow-up time was 37 months (mo) (42 mo for BC and 29 mo for CPRC). The trial met its primary endpoint, demonstrating that denosumab Q12W is non-inferior to Q4W. Median time to first on-trial SSE for arm A was 56.6 mo (95% CI (40.7, not reached [NR]) and for arm B 56.5 mo (95% CI 47.7, NR). The stratified HR and 90% CI calculated using a Cox regression model is 1.023 (0.874, 1.197) with the upper limit remaining below 1.20. Also, for time to first and subsequent on-trial SSE, non-inferiority was shown with a stratified HR 1.043 (90% CI 0.907, 1.198). Safety analysis showed less toxicity for the Q12W arm: Hypocalcemia occurred in 46% (Arm A) vs 30% (Arm B), and ONJ was reported in 8.5% vs 6.9% of pts, respectively. Conclusions: The SAKK 96/12 REDUSE trial demonstrates that a Dmab Q12W schedule, following a 3-month loading phase, is non-inferior to the Q4W regimen in pts with bone-metastatic BC or CRPC. The observed lower rates in ONJ and hypocalcemia indicate a more favorable safety profile for the Q12W schedule. These data indicate that Dmab Q12W represents the new standard of care in pts with bone metastasis from BC or CRPC, offering comparable efficacy while reducing toxicity, treatment burden, and costs. Clinical trial information: NCT02051218 .